Summary/Abstract There is growing evidence suggesting that the epigenetic processes such as histone acetylation may play a role in the alcohol-induced gene regulations and behavior. To date, the studies in animals demonstrated that histone deacetylases (HDACs), at least HDAC2 and HDAC3, could induce histone-related epigenetic changes after the treatment of ethanol. In addition, several studies have shown that HDAC inhibitors could be used to counter ethanol-induced behaviors and the ethanol-induced changes of HDAC levels. We have recently achieved a major research goal by developing a PET imaging agent, [11C]Martinostat that selectively binds to a subset of HDAC enzymes. [11C]Martinostat has been full characterized as a novel and the first PET radiotracer for epigenetic research through rodent imaging, non-human primates (NHPs) imaging and pilot healthy human imaging. We are extremely excited to take a large step forward in understanding epigenetic role in alcoholism by visualizing HDACs in the healthy and dysfunctional human brain in alcohol use disorder (AUD) patients. Together with the our multidisciplinary teams and strong collaborations, we are seeking the support through the R21/R33 mechanism for this high-risk, high-reward study to characterize the density and distribution of key HDACs throughout the brain of healthy subjects and in patients with alcoholism by applying our new PET imaging probe. Our initial data on [11C]Martinostat in humans strongly supports the success of our proposal for clinical imaging in healthy subjects (Aim 1) and in AUD patients (Aim 2 and Aim 3) in R21/R33 phases. PET-MR imaging in humans with [11C]Martinostat will deliver answers to fundamental questions about chromatin modifying enzymes in the living human brain in a way that has not been possible until now and facilitate proof of mechanism/target engagement in novel therapeutic trials.